A Non-Invasive Surrogate Test of OGTT to Screen for Pre-diabetes

描述（由申请人提供）：本提案的长期目标是开发一种廉价的、完全非侵入性的2小时口服葡萄糖耐量试验（2小时OGTT）替代试验，用于识别糖尿病前期个体，以达到预防目的。我们认为，可以根据美国糖尿病协会现行方案口服75 g 13 C标记的葡萄糖溶液，然后测量呼气CO2同位素富集的曲线下面积（AUC）来开发这种测试。由于该测试测量OGTT方案期间葡萄糖和脂质氧化损伤的综合效应，因此它：（i）比当前的2小时OGTT更敏感，并且（ii）与2小时OGTT血糖强烈相关。由于它仅依赖于收集呼吸样本，因此完全是非侵入性的，因此非常适合涉及大量个体的筛查目的。我们的初步数据表明，这是一个很好的替代试验2小时OGTT，但为了进一步进行，我们需要首先建立其内部和个体间的变异性作为恶化的葡萄糖耐量的函数。在I期资助周期（当前申请）期间，我们将在20名男性和女性中实施一项方案，根据标准2小时OGTT血糖，这些男性和女性的血糖范围从血糖正常到糖尿病，目的是在不同的2小时OGTT值下建立所提议的测试的个体内和个体间变异性。在随后的第二阶段资助周期中，我们计划进行适当的方案，以便：（i）建立这种替代试验和2小时OGTT之间的相关性强度，以及（ii）研究这种方法是否可以用于预测葡萄糖耐量受损的发展，以达到预防目的。在第三阶段和非SBIR资金，我们将：（i）建立一个中心设施，生产相关的测试套件，（ii）与选定的糖尿病研究中心建立合作关系，以展示其应用，并使测试提供给社区。公共卫生相关性：2型糖尿病（T2 DM）是一种严重的慢性疾病，影响全球数百万人。预防/延迟糖尿病的发作被认为是糖尿病管理中的重要问题，并且需要在临床症状发作之前在进展过程（前驱糖尿病）的早期选择个体的能力。目前糖尿病前期的诊断是基于空腹血糖或口服葡萄糖耐量试验（OGTT）后2小时血糖。这两种方法识别不同的糖尿病前期亚群，并且对于选择处于风险中的个体都是必要的。美国糖尿病协会不鼓励使用口服葡萄糖耐量试验，因为它在成本、方便性和可重复性方面存在局限性。我们建议开发一种完全无创的替代试验，用于2小时OGTT，该试验基于给予标准剂量的用非放射性稳定同位素13 C6-葡萄糖标记的葡萄糖后的呼吸采样。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to develop an inexpensive, totally non-invasive surrogate test for the 2-h oral glucose tolerance test (2-h OGTT) for the purpose of identifying individuals with pre-diabetes for preventive purposes. We believe that such a test can be developed based on oral administration of a 75-g 13C-labeled glucose solution administered according to the current American Diabetes Association protocol followed by the measurement of the area under the curve (AUC) for breath CO2 isotopic enrichment. Because this test measures the combined effects of impairments in both glucose and lipid oxidation during an OGTT protocol, it: (i) is more sensitive than the current 2-h OGTT, and (ii) correlates strongly with the 2-h OGTT blood glucose. And because it relies solely on collecting breath samples, it is totally non-invasive and thus ideal for screening purposes involving large numbers of individuals. Our preliminary data demonstrate that this is a good surrogate test for the 2-h OGTT, but in order to proceed further we need to first establish its intra- and inter-individual variability as a function of worsening glucose tolerance. During Phase-I funding cycle (the current application), we will conduct a protocol in 20 men and women whose glycemia ranges from normoglycemic to diabetic according to standard 2-h OGTT blood glucose for the purpose of establishing intra- and inter-individual variability of the proposed test at different values of 2-h OGTT. During a subsequent Phase-II funding cycle, we plan to conduct appropriate protocols in order to: (i) establish the strength of the correlation between this surrogate test and the 2-h OGTT, and (ii) investigate whether this approach can be used to predict development of impaired glucose tolerance for preventive purposes. During Phase-III and with non-SBIR funds, we will: (i) establish a central facility to manufacture the relevant test kits, and (ii) develop collaborative relations with selected diabetes research centers in order to demonstrate its applications and make the test available to the community. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2DM) is a serious chronic disease affecting millions of people globally. Prevention/delay of onset of diabetes is considered an important issue in diabetes management and requires the ability to select individuals early in the course of progression (pre-diabetes) before onset of clinical symptoms. Current diagnosis of pre-diabetes is based on either fasting plasma glucose or 2-hour plasma glucose after administration of an oral glucose tolerance test (OGTT). These two methods identify different subsets of pre-diabetics and are both necessary for selection of at-risk individuals. Use of oral glucose tolerance test has been discouraged by the American Diabetes Association because of its limitations related to cost, convenience, and repeatability. We propose to develop a totally non-invasive surrogate test for the 2-h OGTT based on breath sampling after administration of a standard dose of glucose labeled with the non- radioactive stable isotope 13C6-glucose.